Colchicine Increases Ventricular Vulnerability in an Experimental Whole‐Heart Model

The traditional gout medication colchicine has been reported to effectively prevent atrial fibrillation recurrence after atrial fibrillation ablation or cardiac surgery in a few clinical trials. Severe adverse events have not yet been reported. The aim of the present study was to assess possible direct electrophysiological effects in an experimental whole‐heart model. Ten rabbit hearts were isolated and Langendorff‐perfused. Thereafter, colchicine was administered in two concentrations (1 and 3 μM). Eight endo‐ and epicardial monophasic action potentials and a 12‐lead ECG showed a stable QT interval and action potential duration during colchicine infusion. Furthermore, there was no significant increase in dispersion of repolarization. However, colchicine induced a dose‐dependent significant decrease of effective refractory period (ERP; 1 μM: ?19 ms, 3 μM: ?22 ms; p < 0.05). In the present study, acute infusion of colchicine in isolated rabbit hearts resulted in a reduction of ERP in the presence of a stable myocardial repolarization. This led to a significantly elevated inducibility of ventricular fibrillation. In 4 of 10 hearts, incessant ventricular fibrillation occurred. These results suggest a pro‐arrhythmic or toxic effect of colchicine and underline that further clinical studies on potential adverse effects should be conducted before the drug can be recommended for routine use after atrial fibrillation ablation.     

New British Columbia guidelines for supporting sexual health and intimacy in care facilities

Intimacy and sexual expression are an integral part of being human and of healthy living. However, this important aspect of well-being is often overlooked or avoided when a person enters a care facility such as a nursing home, group home, or assisted living residence. This article summarizes the new Supporting Sexual Health and Intimacy in Care Facilities Guidelines, which suggest ways of supporting healthy intimacy and sexuality in care facilities.     

PLGA-PEI nanoparticles for gene delivery to pulmonary epithelium.

Pulmonary gene delivery is thought to play an important role in treating genetically related diseases and may induce immunity towards pathogens entering the body via the airways. In this study we prepared poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles bearing polyethyleneimine (PEI) on their surface and characterized them for their potential in serving as non-viral gene carriers to the pulmonary epithelium. Particles that were synthesized at different PLGA-PEI ratios and loaded with DNA in several PEI-DNA ratios, exhibited narrow size distribution in all formulations, with mean particle sizes ranging between 207 and 231 nm. Zeta potential was strongly positive (above 30 mV) for all the PEI-DNA ratios examined and the loading efficiency exceeded 99% for all formulations. Internalization of the DNA-loaded PLGA-PEI nanoparticles was studied in the human airway submucosal epithelial cell line, Calu-3, and DNA was detected in the endo-lysosomal compartment 6 h after particles were applied. Cytotoxicity of these nanoparticles was dependent on the PEI-DNA ratio and best cell viability was achieved by PEI-DNA ratios 1:1 and 0.5:1. These findings demonstrate that PLGA-PEI nanoparticles are a potential new delivery system to carry genes to the lung epithelium.     

Preliminary clinical results of Descemet membrane endothelial keratoplasty

PURPOSE: To describe the preliminary clinical results of selective transplantation of organ cultured, donor Descemet membrane (DM) carrying autologous corneal endothelium through a 3.5-mm incision, tentatively named Descemet membrane endothelial keratoplasty (DMEK), for the management of corneal endothelial disorders. DESIGN: Nonrandomized clinical study. METHODS: In 10 patients with Fuchs endothelial dystrophy or pseudophakic bullous keratopathy, DMEK was performed. A 3.5-mm clear corneal tunnel incision was made, the anterior chamber was filled with air, and DM was stripped off from the posterior stroma. A 9.0-mm diameter DM roll was harvested from an organ cultured donor corneo-scleral rim, and inserted into a recipient anterior chamber. The donor tissue was gently unfolded, positioned onto the posterior stroma, and secured by completely filling the anterior chamber with air for 30 minutes. RESULTS: At one month, six eyes had a best-corrected visual acuity of 0.5 (20/40) or better, and three eyes reached 1.0 (20/20). At six months, the endothelial cell density averaged 2030 (+/-373) cells/mm(2) (n = 7). Three eyes showed a complete detachment of the donor tissue in the early postoperative course that was managed by removal of the transplant and a secondary Descemet stripping endothelial keratoplasty procedure. CONCLUSION: DMEK may have potential to become the most preferable technique to manage corneal endothelial disorders, because it provides quick and nearly complete visual rehabilitation. Because the donor tissue required can be prepared from organ cultured corneo-scleral rims, the procedure may be readily accessible to most corneal surgeons.     

Formation of transient covalent protein and DNA adducts by quercetin in cells with and without oxidative enzyme activity

This study investigates the role of cellular tyrosinase and/or peroxidase-like oxidative enzyme activity in the covalent binding of quercetin to glutathione, protein, and DNA, as well as the stability of quercetin DNA adducts in time. This was done by studying the formation of glutathionyl quercetin adducts in various in vitro models, and the covalent binding of radiolabeled quercetin to protein and DNA in cells with elevated peroxidase or tyrosinase levels and in cells devoid of nucleotide excision repair (NER). Cells with elevated tyrosinase or peroxidase levels contained approximately 2 times higher levels of covalent quercetin adducts than cells without detectable levels of these oxidative enzymes. However, this difference was smaller than expected based on the differences in tyrosinase and/or peroxidase levels, indicating that these types of oxidative enzyme activities do not play a major role in the cellular pro-oxidant activity of quercetin. Furthermore, quercetin DNA adducts were of transient nature, independent of the presence of NER, suggesting chemical instability of the adducts. Whether this transient nature reflects real reversibility or formation of genotoxic, depurinated sites remains to be investigated at the molecular level. Together, these data indicate that formation of covalent quercetin adducts can be expected in all cells, independent of their oxidative enzyme levels, whereas the transient nature of the DNA adducts formed may limit or cause their ultimate biological impact. If the transient nature represents chemical reversibility of the adduct formation, it would provide a possible explanation for the apparent lack of in vivo carcinogenicity of this in vitro mutagen. Therefore, in vitro mutagenicity studies should focus more on the transient nature of DNA adducts responsible for the mutagenicity in vitro, since this transient nature of DNA adducts may play an essential role in whether the genotoxicity observed in vitro will have any impact in vivo.     

In vitro evaluation of intestinal absorption of desmopressin using drug-delivery systems based on superporous hydrogels

The aim of this study was to investigate and modify the potential of drug-delivery systems based on superporous hydrogel (SPH) for improving the intestinal transport of the peptide drug desmopressin in vitro. The swelling properties and mechanical strength of SPHs were studied. The release profile of desmopressin was investigated by changing the composition of excipients in the formulations. Subsequently, the ability of the SPH-based drug-delivery systems to enhance the transport of desmopressin across porcine intestine was performed in vitro. The swelling properties and mechanical strength of SPHs were affected by the addition of the disintregrant AcDiSol. This disintregrant reduced the swelling ratio to 10% and the time to 80% swelling was retarded by 3-5 min in comparison to the negative control. AcDiSol increased the mechanical strength, according to the increasing of penetration pressure value, the pressure that the punch can penetrate the gel, of the SPHs. The transport of desmopressin across the intestinal mucosa in vitro was enhanced four- and six-fold by applying SPH, with AcDiSol, in the absence and presence of the additional absorption enhancer trimethyl chitosan chloride, respectively, in comparison to the negative control. It is concluded that drug-delivery systems based on SPHs are promising for enhancing the intestinal absorption of desmopressin.     

Ring-testing and Field-validation of a Terrestrial Model Ecosystem(TME) – An Instrument for Testing Potentially Harmful Substances: Effects of Carbendazim on Organic Matter Breakdown and Soil Fauna Feeding Activity

Organic matter (OM) decomposition and soil fauna feeding activity were integrated as functional endpoints into ecotoxicological tests with intact-soil-core Terrestrial Model Ecosystems (TMEs). Cellulose filter paper served as standardized OM and was either inserted into the top soil or placed on the soil surface for a period of up to 16 weeks. Faunal feeding activity was assessed by the bait-lamina method. The fungicide carbendazim, applied at six dosages ranging from 0.36 kg/ha to 87.5 kg a.i./ha, served as a model chemical. To validate the results from the TME test, a field study was run in parallel. In TMEs the cellulose paper inserted into the soil was decomposed faster than under field conditions. The carbendazim-induced effects on OM decomposition in TMEs and in the field were comparable and followed a clear dose-response relationship. The calculated EC50 values after 8 weeks of incubation were 9.5, 7.1 and 2.1 kg carbendazim/ha for grassland TMEs, grassland field and arable TMEs, respectively. The feeding activity of the soil fauna showed a large variability. The EC50 values for the effect of carbendazim on bait-lamina consumption ranged between 2.0 and 56 kg a.i./ha. Effects on decomposition were correlated with effects on enchytraeids and earthworms but not with effects on bait-lamina consumption.     

Locust bean gum safety in neonates and young infants: An integrated review of the toxicological database and clinical evidence

Locust bean gum (LBG) is a galactomannan polysaccharide used as thickener in infant formulas with the therapeutic aim to treat uncomplicated gastroesophageal reflux (GER). Since its use in young infants below 12 weeks of age is not explicitly covered by the current scientific concept of the derivation of health based guidance values, the present integrated safety review aimed to compile all the relevant preclinical toxicological studies and to combine them with substantial evidence gathered from the clinical paediatric use as part of the weight of evidence supporting the safety in young infants below 12 weeks of age. LBG was demonstrated to have very low toxicity in preclinical studies mainly resulting from its indigestible nature leading to negligible systemic bioavailability and only possibly influencing tolerance. A standard therapeutic level of 0.5 g/100 mL in thickened infant formula is shown to confer a sufficiently protective Margin of Safety. LBG was not associated with any adverse toxic or nutritional effects in healthy term infants, while there are limited case-reports of possible adverse effects in preterms receiving the thickener inappropriately. Altogether, it can be concluded that LBG is safe for its intended therapeutic use in term-born infants to treat uncomplicated regurgitation from birth onwards.     

Measurement of stable changes of self-management skills after rehabilitation: a latent state–trait analysis of the Health Education Impact Questionnaire (heiQ™)

Purpose

To assess stable effects of self-management programs, measurement instruments should primarily capture the attributes of interest, for example, the self-management skills of the measured persons. However, measurements of psychological constructs are always influenced by both aspects of the situation (states) and aspects of the person (traits). This study tests whether the Health Education Impact Questionnaire (heiQ?), an instrument assessing a wide range of proximal outcomes of self-management programs, is primarily influenced by person factors instead of situational factors. Furthermore, measurement invariance over time, changes in traits and predictors of change for each heiQ? scale were examined.

Methods

Subjects were N = 580 patients with rheumatism, asthma, orthopedic conditions or inflammatory bowel disease, who filled out the heiQ? at the beginning, the end of and 3 months after a disease-specific inpatient rehabilitation program in Germany. Structural equation modeling techniques were used to estimate latent trait-change models and test for measurement invariance in each heiQ? scale. Coefficients of consistency, occasion specificity and reliability were computed.

Results

All scales showed scalar invariance over time. Reliability coefficients were high (0.80–0.94), and consistency coefficients (0.49–0.79) were always substantially higher than occasion specificity coefficients (0.14–0.38), indicating that the heiQ? scales primarily capture person factors. Trait-changes with small to medium effect sizes were shown in five scales and were affected by sex, age and diagnostic group.

Conclusion

The heiQ? can be used to assess stable effects in important outcomes of self-management programs over time, e.g., changes in self-management skills or emotional well-being.